Seeing X Chromosomes in a New Light
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In recent years, scientists have increasingly appreciated that our cells can vary genetically — a phenomenon called mosaicism.
And X-chromosome inactivation, Dr. Nathans’s pictures show, creates a
genetic diversity that’s particularly dramatic. Two cells side by side
may be using different versions of many different genes. “But there is
also much larger-scale diversity,” Dr. Nathans said.
In
some brains, for example, a mother’s X chromosome was seen dominating
the left side, while the father’s dominated the right. Entire organs can
be skewed toward one parent. Dr. Nathans and his colleagues found that
in some mice, one eye was dominated by the father and the other by the
mother. The diversity even extended to the entire mouse. In some
animals, almost all the X chromosomes from one parent were shut; in
others, the opposite was true.
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“It’s
incredibly important,” said Dr. Willard, the Duke geneticist. “This is
the most stunning display of what Mary Lyon said 50 years ago.”
Dr.
Nathans hopes his colored maps can serve as an atlas for the effects of
X-chromosome inactivation on women’s bodies. Because each X chromosome
carries different variants of the same genes, father-dominated tissues
may behave differently from mother-dominated ones.
How
one cell ends up silencing its mother’s or father’s X chromosome is
still not entirely clear. Scientists are just starting to decipher some
of the key steps in the process. “The knowledge of this is exploding,”
said Dr. Jeannie T. Lee, a Howard Hughes Medical Institute investigator at Harvard Medical School.
Scientists
don’t know how a cell chooses one chromosome or another to silence. But
they’ve identified a number of the molecules that do the silencing. The
leader of this molecular team is known as Xist.
Ever
since it was discovered in the 1990s, scientists have debated how Xist
managed to shut down an entire chromosome. Some researchers suggested
that one Xist molecule landed on one spot on the X chromosome and then
others attached to it, spreading along its length. But recent studies by
Dr. Lee and colleagues show that Xist molecules envelop the X
chromosome like a swarm of bees. “It’s going to all the genes all at
once,” she said.
Once
Xist latches on, it lures other types of molecules. Together they
enshroud the X chromosome. When a cell divides, new copies of the
molecules silence the same chromosome in its descendants.
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Why
women’s cells should bother with such an elaborate dance has also
intrigued scientists. While scientists have proposed a number of
explanations ever since X-chromosome inactivation was discovered, Gabriel A.B. Marais,
an evolutionary biologist at the University of Lyons in France, said
that none fit the current evidence very well. “The situation is very
confusing,” he confessed.
It’s
possible, for example, that males have to increase the production of
proteins from their X chromosome because they have only one copy of its
genes. But this creates a quandary for females, because they may
overdose themselves. They shut down one of the hyperactive X chromosomes
to regain a balance of their own.
Females
might have evolved to choose randomly between their parents’
chromosomes because it gave them more genetic versatility. Sometimes a
gene on one X chromosome is defective. Cells that use the healthy copy
of the X chromosome can compensate. Males, by contrast, are far more
prone to genetic disorders linked to the X chromosome, such as color blindness. With only one X chromosome in their cells, they have no backup.
Dr.
Nathans speculates that using chromosomes from both parents is
especially useful in the nervous system. It could create more ways to
process information. “Diversity in the brain is the name of the game,”
he said.
But
the X chromosome may also pose a risk to women. Dr. Lee and her
colleagues have found that when they shut down Xist in female mice, the
animals were more likely to develop cancer. She suspects that when a
cell stops making Xist, its inactivated X chromosome wakes up. The extra
proteins it makes can drive a cell to grow uncontrollably.
“That
has bearing on stem cell therapy,” she added. When stem cells are
reared in the lab, they sometimes stop making Xist as well. Dr. Lee is
concerned that female stem cells may rouse sleeping X chromosomes, with
devastating consequences.
Before
stem cells can be safely used in medical treatments, we may finally
need to solve the mystery that Henking originally labeled with an X.
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Author / Source: Carl Zimmer for NYTimes